Plasmacytoid dendritic cells (pDCs) are a rare lymphocyte DC lineage that produces the majority of type I interferon (IFN) during viral infections. Despite extensive study in HIV and SIV infection, the role of pDCs in pathogenesis remains largely unknown. pDCs and IFN may orchestrate a strong antiviral effect that may contribute to the early control of HIV/SIV replication via IFN-induced retroviral restriction factos. However, unabated pDC activation and IFN production may influence the chronic immune activation that is a key factor driving HIV pathogenesis and virus persistence during antiretroviral therapy (ART). We have recently published studies in SIV-infected non-human primates that demonstrate that SIV-related immune activation is strongly linked to the antiviral interferon (IFN) response, and to pDCs. We have also shown that in vivo inhibition of IFN signaling or pDC trafficking to the rectal mucosa can reduce immune activation in SIV infected rhesus macaques. To further this line of research, we have developed a novel monoclonal antibody (12B) that specifically depletes pDCs in rhesus macaques. This proposal will test the hypothesis that the elimination of pDCs, in vivo, from SIV-infected rhesus will substantially reduce immune activation. This hypothesis will be addressed by the experiments in the following Specific Aims: Aim1 - Establish a robust mAb 12B dosing regimen to maximize pDC depletion in blood and tissues; and Aim 2 - Determine the effect of pDC depletion on immune activation, CD4+ depletion and control of viral replication. At the conclusion of these exploratory studies, we will have achieved the following objectives: (i) definitively established the role of pDCs and IFN in driving immune activation and CD4+ T cell depletion (ii) developed a novel research tool for immunological studies in NHPs, and; (iii) characterized the potential of this reagent for translation into clinical trials.